Our long-term goal is to understand how retinal circuits perform the computations underlying healthy vision. The immediate goal of this proposal is to understand how retinal circuits adjust their properties to the contrast of a visual scene. Contrast adaptation is important for visual processing across eye fixations and between different environments: it increases sensitivity at low contrast to improve the signal-to-noise ratio, and it decreases sensitivity at high contrast to prevent response saturation. Presently, we know relatively little about the cellular and synaptic basis for contrast adaptation in the mammalian retina. This proposal comprises two specific aims that will generate novel insights into the synaptic mechanisms underlying contrast adaptation by integrating synapse- and circuit-level analyses of retinal signaling. In one approach, responses to contrast stimulation of photoreceptors will be recorded in specific types of retinal interneurons identified by genetic expression of fluorescent proteins and visualized by two-photon laser-scanning microscopy. In a second approach, we will use optogenetic control of subtypes of interneurons to examine transmission at specific synapses. Using these complementary approaches, Specific Aim 1 will determine the mechanisms for contrast adaptation in dim light by probing a specialized pathway for rod vision. Specific Aim 2 will determine the mechanisms for contrast adaptation at brighter light levels by probing parallel pathways for cone vision. Relevance to Public Health: Understanding how contrast adaptation is implemented by retinal synapses and circuits generates fundamental information about the neural basis of vision and informs the design of retinal prosthetics and the study of animal models of human retinal diseases. A goal of vision research is the development of gene-based therapies for treating blindness caused by photoreceptor degeneration (e.g., retinitis pigmentosa). A promising therapy of this sort is the generation of light sensitivity in retinal interneurons using virally-mediated expression of channelrhodopsin-2 (ChR2), a light-gated cation channel. We will express ChR2 in interneurons to study synaptic interactions in retinal circuits; by design, we will compare photoreceptor- and ChR2-mediated circuit outputs. Thus, we will generate critical information about the range of visual signals that could be encoded by a retina in which ChR2 is the only light sensor. We address three goals of the Retinal Diseases Program in the National Plan for Eye and Vision Research: 1) determining potential therapeutic strategies for treatment of retinitis pigmentosa, 2) increasing understanding of post-photoreceptor adaptation (i.e., gain control in neural circuits), and 3) increasing understanding of how inter-cellular interactions in neural networks generate signals that are interpretable as visual images.